I. Field of the Invention
The present invention relates generally to microbiology, pharmaceutical chemistry and antibiotic formulations. More specifically, the present invention relates to inositol hexakisphosphate analogs.
II. Description of the Related Art
Clostridium difficile is a Gram-positive, spore-forming anaerobic bacillus that is a common cause of nosocomial antibiotic-associated diarrhea and is the etiologic agent of pseudomembranous colitis. The disease ranges from mild diarrhea to life threatening fulminating colitis. Antibiotic use in patients results in a reduction of the commensal gut microflora. C. difficile is resistant to most antibiotics, which gives it a competitive advantage over normal bacterial flora resulting in its proliferation and toxin production.
C. difficile enterotoxins (TcdA and TcdB) are the major cause of the disease since toxin-deficient strains are avirulent. Standard therapy depends on treatment with vancomycin or metronidazole, neither of which is fully effective. Moreover, up to 35% of patients infected with C. difficile relapse following treatment. The primary treatment option for recurrent C. difficile infection (CDI) is still metronidazole or vancomycin. C. difficile infection accounts for approximately 25% of cases of antibiotic-associated diarrhea and the incidence of infection is rising steadily in North America, with yearly costs in the U.S. estimated at $3.2 billion. Several recent hospital outbreaks of C. difficile infection associated with high morbidity and mortality rates have been attributed to the widespread use of broad-spectrum antibiotics. The emergence of new and more virulent C. difficile strains also contributes to the increased incidence and severity of the disease. Because of the steadily rising incidence and severity, C. difficile infection is an important emerging drug-resistance associated disease.
The incidence of C. difficile carriage in healthy adults is around 3-5%. By contrast, in hospitalized adults taking antibiotics, the rate of colonization increases substantially to 20-40%, and is associated with a high disease burden. According to the U.S. Agency of Healthcare Research and Quality (AHRQ), the prevalence of hospital patients infected with C. difficile jumped 200% from 2000 to 2005, which follows a 74% increase from 1993 to 2000. This rapid increase in C. difficile infection cases is attributed to the use of broad-spectrum antibiotics and/or the emergence of new hypervirulent C. difficile strains, such as BI/NAP1/027.
C. difficile infection is associated with a wide spectrum of clinical outcomes ranging from asymptomatic carriage to fulminant and fatal colitis. Severe C. difficile infection may also be associated with systemic manifestations including marked leukocytosis, hypotension, renal failure, respiratory failure, coagulopathy, and lactic acidosis. Refractory cases, not responding to vancomycin and/or metronidazole treatment is not uncommon. A recent study found that 22.1% of hospital in-patients with C. difficile infection had severe disease. The incidence of in-hospital deaths in the cohort of patients with C. difficile infection was 12.1%, and mortality caused primarily by C. difficile infection was 4.0%. Surgical intervention in the form of sub-total colectomy can be life-saving in severe, fulminant, or refractory C. difficile infection. However, patients with severe C. difficile infection are typically elderly, critically ill, and are at high risk for surgical and anesthetic complications.
Several reports have described clinical improvement following use of passive antitoxin immunotherapy with normal pooled intravenous immunoglobulin to avoid surgery and prevent death. More recently, passive immunotherapy using human IgG monoclonal antitoxins was reported to be effective in preventing recurrent C. difficile infection. However, it did not confer protection against toxin activity, and the length of hospitalization was not significantly reduced. Other options, such as probiotics and anion-exchange resins, have limited efficacy and are potentially harmful. Complementary therapy is therefore urgently warranted to neutralize toxin activity. Experimental therapy currently under clinical development includes toxin-absorbing polymers and new antibiotics.
There is a recognized need in the art for alternative therapies for Clostridium difficile infections. The present invention fulfills this long-standing need and desire in the art by providing inositol hexakisphosphate-based compounds effective to treat C. difficile infections and to neutralize its toxins.